Trmt61a, along with Trmt6, forms an RNA N1-methyladenosine (m1A)-generating methyltransferase complex. m1A is a post-transcriptional RNA modification that impacts RNA processing, structure, and functions [2,4]. This complex is involved in various biological processes, such as translation regulation, as it can modify tRNA and mRNA, influencing protein synthesis [3,5].

In aged murine hematopoietic stem cells (HSCs), the TRMT6-TRMT61A complex increases due to declined CRL4DCAF1-mediated ubiquitination degradation signaling. Enforced TRMT6-TRMT61A impairs HSCs through 3'-tiRNA-Leu-CAG and subsequent RIPK1-RIPK3-MLKL-mediated necroptosis cascade. Necroptosis deficiency ameliorates HSC self-renewal capacity, indicating the complex's non-canonical role in HSC aging [1]. In T cells, conditional deletion of the Trmt61a gene in mouse CD4+ T cells causes MYC protein deficiency and cell cycle arrest, disrupting T cell expansion upon antigen stimulation and alleviating colitis in a mouse model. This shows that Trmt61a-mediated tRNA-m1A58 modification promotes T cell expansion via efficient MYC protein synthesis [3]. In bladder cancer cell lines, depletion of TRMT6/TRMT61A reduces proliferation capacity and cell displacement, and compromises cell survival after induction of cellular stress, suggesting an oncogenic role in bladder cancer [6].

In summary, Trmt61a, as part of the TRMT6-TRMT61A complex, plays crucial roles in regulating processes like HSC function, T cell expansion, and cancer cell behavior. Gene knockout and conditional knockout mouse models have been instrumental in revealing its functions in HSC aging, T cell-mediated pathogenesis, and bladder cancer, providing insights into potential therapeutic targets for related diseases [1,3,6].

References:

1. He, Hanqing, Wang, Yuqian, Zhang, Xiaoting, Yi, Chengqi, Wang, Jianwei. 2024. Age-related noncanonical TRMT6-TRMT61A signaling impairs hematopoietic stem cells. In Nature aging, 4, 213-230. doi:10.1038/s43587-023-00556-1. https://pubmed.ncbi.nlm.nih.gov/38233630/

2. Li, Jiexin, Zhang, Haisheng, Wang, Hongsheng. 2022. N1-methyladenosine modification in cancer biology: Current status and future perspectives. In Computational and structural biotechnology journal, 20, 6578-6585. doi:10.1016/j.csbj.2022.11.045. https://pubmed.ncbi.nlm.nih.gov/36467585/

3. Liu, Yongbo, Zhou, Jing, Li, Xiaoyu, Wu, Yuzhang, Li, Hua-Bing. 2022. tRNA-m1A modification promotes T cell expansion via efficient MYC protein synthesis. In Nature immunology, 23, 1433-1444. doi:10.1038/s41590-022-01301-3. https://pubmed.ncbi.nlm.nih.gov/36138184/

4. Liu, Yafeng, Zhang, Shujun, Gao, Xiaohui, Gu, Xinyu, Hu, Xinjun. 2024. Research progress of N1-methyladenosine RNA modification in cancer. In Cell communication and signaling : CCS, 22, 79. doi:10.1186/s12964-023-01401-z. https://pubmed.ncbi.nlm.nih.gov/38291517/

5. Safra, Modi, Sas-Chen, Aldema, Nir, Ronit, Stern-Ginossar, Noam, Schwartz, Schraga. 2017. The m1A landscape on cytosolic and mitochondrial mRNA at single-base resolution. In Nature, 551, 251-255. doi:10.1038/nature24456. https://pubmed.ncbi.nlm.nih.gov/29072297/

6. Monshaugen, Ida, Luna, Luisa, Rhodes, Jayden, Klungland, Arne, Ougland, Rune. 2024. Depletion of the m1A writer TRMT6/TRMT61A reduces proliferation and resistance against cellular stress in bladder cancer. In Frontiers in oncology, 13, 1334112. doi:10.3389/fonc.2023.1334112. https://pubmed.ncbi.nlm.nih.gov/38304034/